The University of Southampton
University of Southampton Institutional Repository

Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis

Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis
Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF), the prototypic progressive fibrotic interstitial lung disease, is thought to be a consequence of repetitive micro-injuries to an ageing, susceptible alveolar epithelium. Ageing is a risk factor for IPF and incidence has been demonstrated to increase with age. Decreased (macro)autophagy with age has been reported extensively in a variety of systems and diseases, including IPF. However, it is undetermined whether the role of faulty autophagy is causal or coincidental in the context of IPF. Here we report that in alveolar epithelial cells inhibition of autophagy promotes epithelial-mesenchymal transition (EMT), a process implicated in embryonic development, wound healing, cancer metastasis and fibrosis. We further demonstrate that this is attained, at least in part, by increased p62/SQSTM1 expression that promotes p65/RELA mediated-transactivation of an EMT transcription factor, Snail2 (SNAI2), which not only controls EMT but also regulates the production of locally acting profibrogenic mediators. Our data suggest that reduced autophagy induces EMT of alveolar epithelial cells and can contribute to fibrosis via aberrant epithelial–fibroblast crosstalk
2041-4889
1-11
Hill, Charlotte
6d1cfed3-11b1-48af-b171-b8726ab673eb
Li, Juanjuan
7888cf96-2102-4b8c-b719-5dd71f4c359d
Liu, Dian
cb5fbedf-d94c-4527-81a6-db6b52e61438
Conforti, Franco
28bf123c-e42a-4fb5-8b26-f79e1095c586
Brereton, Christopher, J
948ca4ea-b04c-4b7a-bfe4-f79f184d7e43
Yao, Liudi
3c9ce766-5334-49f7-9517-c4dc2013f933
Zhou, Yilu
1878565d-39e6-467d-a027-7320bf4cdaf2
Alzetani, Aiman
04d65796-5c8e-4c5b-aeeb-ea093c118f03
Chee, Serena, Jamie Tzu Wen
51a261fc-2b72-43cc-98dd-79617de7573b
marshall, ben
a5cf0614-864b-4a1e-9148-e8c13e288e72
Fletcher, Sophie
92048e5c-6c10-4572-ab69-81601e9cb0f2
Hancock, David
89f3a3cb-7f88-4f6e-b333-7315aab55ba1
Ottensmeier, Christian
42b8a398-baac-4843-a3d6-056225675797
Steele, Andrew
4349f6aa-2e3a-49a8-be73-7716056ae089
Downward, Julian
3f89cf74-9e21-4113-8f3c-995b1a6ef4ab
Richeldi, Luca
47177d9c-731a-49a1-9cc6-4ac8f6bbbf26
Lu, Xin
b1d7340f-62aa-402b-be6e-78b63af9eea6
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Jones, Mark
a1264258-5fa5-4063-95e1-d7ff7c52a2de
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Hill, Charlotte
6d1cfed3-11b1-48af-b171-b8726ab673eb
Li, Juanjuan
7888cf96-2102-4b8c-b719-5dd71f4c359d
Liu, Dian
cb5fbedf-d94c-4527-81a6-db6b52e61438
Conforti, Franco
28bf123c-e42a-4fb5-8b26-f79e1095c586
Brereton, Christopher, J
948ca4ea-b04c-4b7a-bfe4-f79f184d7e43
Yao, Liudi
3c9ce766-5334-49f7-9517-c4dc2013f933
Zhou, Yilu
1878565d-39e6-467d-a027-7320bf4cdaf2
Alzetani, Aiman
04d65796-5c8e-4c5b-aeeb-ea093c118f03
Chee, Serena, Jamie Tzu Wen
51a261fc-2b72-43cc-98dd-79617de7573b
marshall, ben
a5cf0614-864b-4a1e-9148-e8c13e288e72
Fletcher, Sophie
92048e5c-6c10-4572-ab69-81601e9cb0f2
Hancock, David
89f3a3cb-7f88-4f6e-b333-7315aab55ba1
Ottensmeier, Christian
42b8a398-baac-4843-a3d6-056225675797
Steele, Andrew
4349f6aa-2e3a-49a8-be73-7716056ae089
Downward, Julian
3f89cf74-9e21-4113-8f3c-995b1a6ef4ab
Richeldi, Luca
47177d9c-731a-49a1-9cc6-4ac8f6bbbf26
Lu, Xin
b1d7340f-62aa-402b-be6e-78b63af9eea6
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Jones, Mark
a1264258-5fa5-4063-95e1-d7ff7c52a2de
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e

Hill, Charlotte, Li, Juanjuan, Liu, Dian, Conforti, Franco, Brereton, Christopher, J, Yao, Liudi, Zhou, Yilu, Alzetani, Aiman, Chee, Serena, Jamie Tzu Wen, marshall, ben, Fletcher, Sophie, Hancock, David, Ottensmeier, Christian, Steele, Andrew, Downward, Julian, Richeldi, Luca, Lu, Xin, Davies, Donna, Jones, Mark and Wang, Yihua (2019) Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis. Cell Death and Disease, 10 (8), 1-11. (doi:10.1038/s41419-019-1820-x).

Record type: Article

Abstract

Idiopathic pulmonary fibrosis (IPF), the prototypic progressive fibrotic interstitial lung disease, is thought to be a consequence of repetitive micro-injuries to an ageing, susceptible alveolar epithelium. Ageing is a risk factor for IPF and incidence has been demonstrated to increase with age. Decreased (macro)autophagy with age has been reported extensively in a variety of systems and diseases, including IPF. However, it is undetermined whether the role of faulty autophagy is causal or coincidental in the context of IPF. Here we report that in alveolar epithelial cells inhibition of autophagy promotes epithelial-mesenchymal transition (EMT), a process implicated in embryonic development, wound healing, cancer metastasis and fibrosis. We further demonstrate that this is attained, at least in part, by increased p62/SQSTM1 expression that promotes p65/RELA mediated-transactivation of an EMT transcription factor, Snail2 (SNAI2), which not only controls EMT but also regulates the production of locally acting profibrogenic mediators. Our data suggest that reduced autophagy induces EMT of alveolar epithelial cells and can contribute to fibrosis via aberrant epithelial–fibroblast crosstalk

Text
Hill et al CDDis 2019 - Accepted Manuscript
Available under License Creative Commons Attribution.
Download (18MB)
Text
s41419-019-1820-x - Version of Record
Available under License Creative Commons Attribution.
Download (6MB)

More information

Accepted/In Press date: 18 July 2019
Published date: 7 August 2019

Identifiers

Local EPrints ID: 433093
URI: https://eprints.soton.ac.uk/id/eprint/433093
ISSN: 2041-4889
PURE UUID: 714fe3b2-84ae-4796-8fd9-e6a972cc82ae
ORCID for Andrew Steele: ORCID iD orcid.org/0000-0003-0667-1596
ORCID for Donna Davies: ORCID iD orcid.org/0000-0002-5117-2991
ORCID for Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648

Catalogue record

Date deposited: 07 Aug 2019 16:30
Last modified: 03 Dec 2019 02:07

Export record

Altmetrics

Contributors

Author: Charlotte Hill
Author: Juanjuan Li
Author: Dian Liu
Author: Franco Conforti
Author: Christopher, J Brereton
Author: Liudi Yao
Author: Yilu Zhou
Author: Aiman Alzetani
Author: Serena, Jamie Tzu Wen Chee
Author: ben marshall
Author: Sophie Fletcher
Author: David Hancock
Author: Andrew Steele ORCID iD
Author: Julian Downward
Author: Luca Richeldi
Author: Xin Lu
Author: Donna Davies ORCID iD
Author: Mark Jones
Author: Yihua Wang ORCID iD

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×